In the wake of antimicrobial resistance and the severe lack of new antibiotics being discovered, researchers have turned to alternative strategies.
Antimicrobial peptides (AMPs) are a part of nature’s own defences against bacterial infections. These peptides are small proteins that can create pores in the bacterial membrane or enter the cell and interfere with essential cellular processes. They are generally produced at the site of infection and act locally.
AMPs are produced by all virtually all living organisms, from mould to man, and many of these are structurally similar in many different species. In humans, they are a part of the innate immune system, the first line of defence against infections. The innate immune system responds to threats immediately and non-specifically. The second line of defence is the adaptive immune system, which involves production of specific antibodies and requires a few days to mount a full-scale response.
Challenges for antimicrobial peptides as therapy
Unfortunately, creating therapies with AMPs is not unproblematic due to their peptide nature. In general, peptide drugs must be given either by injection or directly into the affected tissue. AMPs are no exception to this rule.
Peptides only survive a few hours in the body and also penetrate poorly into tissues. Taken as pills, peptides are broken down in the small intestine and do enter the clood stream. This makes achieving sufficient amounts of a peptide drug for longer periods of time very difficult. This makes it necessary to give several injections or infusions per day. Topical administration is easier, and thus therapies like applying AMP-rich honey on severe burns have been tried more extensively.
It has been generally believed that resistance to AMPs is more difficult to acquire for bacteria for at least two reasons:
- AMPs kill bacteria rapidly, leaving little time for adaption for the bug
- AMPs have multiple targets in the bacteria, so even if one target is altered, other targets are still available
Resistance development in new experiments
In a paper published in January 2017, researchers challenged this belief. They cultured strains of Staphylococcus aureus (MRSA) in conditions that resemble the conditions in the human body better than normal laboratory conditions. The bacteria were exposed to four different AMPs from different sources (plant, human, pig), for a total of seven days. The concentration of AMP was selected to be 30% of killing activity for the first 3-4 days, after which the concentration was increased by 50% for the next 3-4 days.
Within that week of experiment, several varieties of bacteria resistant to the AMPs emerged. Later analyses showed a multitude of genetic changes, which also lead to resistance to other AMPs as well as antibiotics. The changes were stable, meaning that the resistance was maintained even in the absence of AMPs. Furthermore, the modification did not change either the growth rate of the bacteria or its capability to cause disease, virulence.
Is resistance inevitable?
The experiment could be criticised for its setup – the selection of AMP concentration and use of only one or two peptides at a time. This kind of setup is more optimised for selecting resistance than to reflect the conditions during infection, but it does highlight an important process. In real life, the development of resistance is probably slower but still as relentless. If AMPs are misused in the same way as antibiotics have been, resistance is inevitable.
Importantly, given the structural likeness of AMPs across the whole tree of life, resistance to one peptide is likely to cause resistance others as well, so called cross-resistance. Resistance to an AMP or AMP-like drug may not only contribute to increasing multiresistance but also disarm the human immune system. This would have devastating consequences for anyone who encounters these bacteria.
Kubicek-Sutherland JZ, Lofton H, Vestergaard M, Hjort K, Ingmer H, Andersson DI. “Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides.” Journal of Antimicrobial Chemotherapy 2017 Jan;72(1):115-127
More from "2017"
- Role of pharmacists in stopping antimicrobial resistance
- ReAct Asia Pacific media briefing: 40 journalists in Jakarta interested in antibiotic resistance
- ReAct Latin America launches book with a One Health perspective
- ReAct Africa walks for antibiotic awareness
- World Antibiotic Awareness Week: focus on non-human use
- Antibiotics in animal agriculture
- Lessons learned from 20 years of working to improve antibiotic use in Sweden
- Member States to discuss innovation, access and conservation of antibiotics at the WHO
- The state of Kerala will develop India’s first subnational action plan on AMR
- ReAct during World Antibiotic Awareness Week 2017
- From ReAct Africa Conference: summary of key takeaways
- Antibiotic resistance strikes hardest at the poor
- Ensuring action on the AMR Global Action Plan
- ReAct meets the European Commissioner for Health
- Antibiotic stewardship in South East Asia
- From ReAct Africa Conference: 6 gaps and 7 key outputs how to make implementation of NAPs on AMR possible
- Crucial stakeholder meeting in India: how to get the Indian NAP on AMR from words into action
- Conference in Ecuador: health, food, the planet and the microbial world
- The world is running out of antibiotics – new report from WHO
- Food, microbes and health
- ReAct’s priorities in what promises to be an important autumn for antibiotic resistance
- Many countries identify antimicrobial resistance as an obstacle on their way to implementing Agenda 2030
- Important African conference: How will we be able implement National Action Plans on Antimicrobial Resistance?
- Antibiotic resistance: national workshop in India for voluntary organizations
- Resistance to last-line antibiotics
- Essential Diagnostics List (EDL) to be developed
- Media workshop in Ecuador: a success
- ReAct withdraws from IMI project DRIVE-AB
- Microbes – friend, foe or both?
- ReAct Asia Pacific hosts workshop on antimicrobial resistance in the farm sector
- Successful antimicrobial resistance media training in Nairobi, Kenya
- Mother Earth, One Health – International Encounter in Argentina
- Key take-aways from the World Health Assembly 2017 on antimicrobial resistance
- National action plans and global AMR framework on the agenda as 70th World Health Assembly kicks off next week
- ReAct co-hosts side event during World Health Assembly
- ReAct supports countries in the development of National Action Plans on AMR
- Lack of access to old antibiotics drives antibiotic resistance development and impairs patient outcomes
- Hand hygiene saves lives
- The Swedish Government awards Reward Medal to Professor Otto Cars
- Presentation of the Alforja Educativa Validation Project enthuses students
- New antibiotics in the news
- Free online course: Antibiotic Resistance: the Silent Tsunami
- Tell Our Bac-Stories!
- India’s link between tuberculosis and antibiotic resistance
- Environmental effects of antibiotics in sewage
- Professor Larsson on India’s National Action Plan on AMR and emissions from antibiotics production
- India’s new National Action Plan on Antimicrobial Resistance
- Professor Otto Cars to serve as Expert in UN Inter-Agency Coordination Group on Antimicrobial Resistance
- Johns Hopkins Bloomberg School of Public Health is looking for a Research Associate
- Could the use of Antimicrobial Peptides create resistance to ourselves?
- Boston Consulting Group report shies away from addressing affordable access and stewardship
- WHO Releases Priority Pathogens List
- Antibiotic Smart Use project nominated for global UN Award
- European Commission diagnostic prize winner announced
- Recap of WHO 140th Executive Board meeting
- New collaboration on strategies for tackling antibiotic resistance